In vivo model to predict human fetal toxicity of xenobiotics : Establishment and evaluation of humanized mice carrying multiple forms of human fetal drug metabolizing enzymes.

外源生物对人类胎儿的毒性大多是不可预测的，因为存在于人类胚胎中的药物代谢酶，如细胞色素P450(CYP)，在啮齿动物胚胎中不存在。为了建立和预测人类胎儿毒性的动物模型，我们通过转基因技术将多种形式的人胎儿药物代谢酶引入小鼠体内。建立了4个携带人胎酶的转基因小鼠品系。在36P系小鼠胚胎中，检测到人细胞色素P1A1、细胞色素P1B1、细胞色素P3A7、环氧合酶-1和环氧合酶-2在基因水平上的表达。在妊娠第9天，用人类已知的致畸剂沙利度胺(100 mg/kg体重)处理36P雌性小鼠，可增加胚胎的死亡或吸收。因此，这些人源化的小鼠可能成为预测化学物质对人类胎儿毒性的合适模型。

Most of the human fetal toxicities of xenobiotics are unpredictable, since drug metabolizing enzymes such as cytochrome P450 (CYP), which are present in human fetuses, do not exist in rodent fetuses. In order to establish and animal model to predict human fetal toxicities, we introduced multiple forms of human fetal drug metabolizing enzymes into mice by transgenic technique. Four transgenic lines of mice carrying human fetal enzymes were established. In the 36p line of mice, the expression of human CYP1A1, CYP1B1, CYP3A7, cyclooxygenase (COX)-1 and COX-2 at mRNA levels were detected in the mouse fetuses. Treatment of the 36p female mice with a single dose of thalidomide (100 mg/kg b wt.), a well-known teratogen in humans, on gestational day 9 resulted in the increased deaths or the resorptions of embryos. Thus, these humanized mice may become a suitable model to predict human fetal toxicities of chemicals.